(R)‐1‐(4‐chloro‐2‐(3‐methyl‐1H‐pyrazol‐1‐yl)phenyl)‐2,2,2‐trifluoroethan‐1‐ol [(R)‐2] is a key chiral intermediate in the synthesis of telotristat ethyl, an anti‐carcinoid syndrome drug. However, the synthetic methods for (R)‐2 mainly include chemical reductions, rarely involving biocatalysis or bioreduction until now. Here, we report a method for obtaining (R)‐2 by biocatalytic reduction of corresponding prochiral acetophenone (1) with bulky o‐substitution using recombinant Lactobacillus fermentum short‐chain dehydrogenase/reductase 1 (LfSDR1) as a biocatalyst. Further engineering of LfSDR1 variants could access asymmetric reduction of 1 and yield (R)‐2 with a >99% ee and a >99% conversion. In addition, through the test of different co‐solvents and a series of initial substrate concentrations, substrate 1 with the concentration of 60 g/L can be completely converted into (R)‐2 on a preparative scale (1.13 g, 3.93 mmol, 75.6% isolated yield) in 24 hours. This study presents an efficient enzymatic process for the biocatalytic synthesis of key chiral intermediate (R)‐2 in the synthesis of telotristat ethyl.

中文翻译：

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开发一种用于合成telotristat乙基关键中间体的酶促方法

（R）-1-（4-氯-2-（3-甲基-1H-吡唑-1-基）苯基）-2,2,2-三氟乙烷-1-醇[（R）-2 ]是关键手性中间体，用于合成抗类癌综合症药物telotristat乙基。但是，（R）-2的合成方法主要包括化学还原，到目前为止很少涉及生物催化或生物还原。在这里，我们报告了一种使用重组发酵乳杆菌短链脱氢酶/还原酶1（Lf）通过生物催化还原相应的前手性苯乙酮（1）并进行大体积邻位取代获得（R）-2的方法。SDR1）作为生物催化剂。Lf SDR1变体的进一步工程化可以实现不对称降低1和产生（R）-2，ee大于99％，转化率大于99％。此外，通过测试不同的助溶剂和一系列初始底物浓度，可以以制备规模将底物1的浓度完全转换为（R）-2（1.13 g，3.93 mmol，在24小时内分离出75.6％的产率）。这项研究提出了一种高效的酶促方法，用于在三端三唑乙基的合成中生物催化合成关键的手性中间体（R）-2。